Editing Marfan syndrome
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*Flo Hyman | *Flo Hyman | ||
**Died of aortic rupture in the middle of a volleyball match. | **Died of aortic rupture in the middle of a volleyball match. | ||
- | http:// | + | http://media.photobucket.com/image/flo%20hyman/cougarcards/1977‐79SportscasterFloHyman12.jpg |
===Mode of inheritance=== | ===Mode of inheritance=== | ||
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*'''25% de novo mutations''' | *'''25% de novo mutations''' | ||
*No Documented Cases of Non‐Penetrance | *No Documented Cases of Non‐Penetrance | ||
- | *Many different | + | *Many different missense mutations have been observed (allelic heterogeneity). |
*At least one known splicing mutation: IVS63+373 mutation creates an intronic GT sequence as a new acceptor site at the 5’ terminus and results in generation of a pseudoexon. | *At least one known splicing mutation: IVS63+373 mutation creates an intronic GT sequence as a new acceptor site at the 5’ terminus and results in generation of a pseudoexon. | ||
**This resulted in a 93bp insertion between 8,379 & 8,380 (junction between exons 63 & 64) | **This resulted in a 93bp insertion between 8,379 & 8,380 (junction between exons 63 & 64) | ||
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===Single important gene=== | ===Single important gene=== | ||
*15q21.1: FBN1 gene codes for Fibrillin‐1 | *15q21.1: FBN1 gene codes for Fibrillin‐1 | ||
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*Fibrillin is present in the suspensory ligament, eleastic connective tissue (aorta & ligaments) and periosteum | *Fibrillin is present in the suspensory ligament, eleastic connective tissue (aorta & ligaments) and periosteum | ||
*320 kDa glycoprotein, 2,871 AA | *320 kDa glycoprotein, 2,871 AA | ||
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===Pathogenesis=== | ===Pathogenesis=== | ||
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===Phenotypic information=== | ===Phenotypic information=== | ||
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====Ocular Abnormalities==== | ====Ocular Abnormalities==== | ||
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*Aortic Diliatation | *Aortic Diliatation | ||
**Enlargement | **Enlargement | ||
+ | *http://www.avnrt.com/gigs/marfan1.gif | ||
**Regurgitation | **Regurgitation | ||
**Aneurysm | **Aneurysm | ||
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*Walker Murdoch http://yogatmanbarcelona.wordpress.com/2009/11/24/tu‐medula‐espinal‐ii‐lordosis/ Walker‐(wrists) | *Walker Murdoch http://yogatmanbarcelona.wordpress.com/2009/11/24/tu‐medula‐espinal‐ii‐lordosis/ Walker‐(wrists) | ||
*Steinberg (thumbs) | *Steinberg (thumbs) | ||
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===Diagnosis=== | ===Diagnosis=== | ||
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*It is an angiotensin II type 1 receptor antagonist; that is, it keeps angiotensin II from binding to it's type 1 receptor. | *It is an angiotensin II type 1 receptor antagonist; that is, it keeps angiotensin II from binding to it's type 1 receptor. | ||
**Recall that angiotensin II causes increased activity of the triple-cotransporter at the renal tubules. | **Recall that angiotensin II causes increased activity of the triple-cotransporter at the renal tubules. | ||
- | * | + | *Losartan also blocks the actions of TGF‐β. |
*In a mouse model, losartan inhibits aortic aneurysms (unfortunately common in pts with Marfan syndrome). | *In a mouse model, losartan inhibits aortic aneurysms (unfortunately common in pts with Marfan syndrome). | ||
*Clinical trials are ongoing. | *Clinical trials are ongoing. | ||
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===Recent research=== | ===Recent research=== | ||
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**Neonatal Marfan syndrome | **Neonatal Marfan syndrome | ||
**Familial arachnodactyly | **Familial arachnodactyly | ||
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**Autosomal dominant ectopic lentis | **Autosomal dominant ectopic lentis | ||
**MASS phenotype (Marfanoid signs involving '''m'''itral valve, '''a'''orta, '''s'''keletal, and '''s'''kin). | **MASS phenotype (Marfanoid signs involving '''m'''itral valve, '''a'''orta, '''s'''keletal, and '''s'''kin). | ||
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*So, like FGFR3, there is lots of heterogeneity when one looks at the gene. | *So, like FGFR3, there is lots of heterogeneity when one looks at the gene. | ||
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*Congenital contractural arachnodactyly (FBN2) | *Congenital contractural arachnodactyly (FBN2) | ||
**Clinical presentation overlaps a bit with Marfan syndrome | **Clinical presentation overlaps a bit with Marfan syndrome | ||
- | + | **Arachnodactyly (really long, skinny fingers), pectus deformaties, scoliosis, etc. | |
- | + | **Some young pts have aortic root dilitation | |
- | **Caused by mutation in homologous gene to FBN1 | + | **Caused by mutation in homologous gene to FBN1: FBN2. |
===Questions and answers=== | ===Questions and answers=== | ||
*What are the requirements for a clinical diagnosis of Marfan Syndrome? | *What are the requirements for a clinical diagnosis of Marfan Syndrome? | ||
*What signaling pathway is affected in Marfan Syndrome? | *What signaling pathway is affected in Marfan Syndrome? |